Endothelin (ET) is a highly potent vasoconstrictor peptide synthesized and released by the vascular endothelium. Endothelin exists as three isoforms, ET- 1, ET-2 and ET-3 (unless otherwise stated, "endothelin" shall mean any or all of the isoforms of endothelin). Endothelin has profound effects on the cardiovascular system, and in particular, the coronary, renal and cerebral circulation. Elevated or abnormal release of endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of cardiovascular, cerebrovascular, respiratory and renal pathophysiology. Elevated levels of endothelin have been reported in plasma from patients with essential hypertension, acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis, and patients with uraemia undergoing dialysis.
Many studies suggest that endothelin receptor antagonists would offer a unique approach toward the pharmacotheraphy of hypertension, renal failure, ischemia-induced renal failure, sepsis-endotoxin-induced-renal failure, prophylaxis and/or treatment of radio-contrast-induced renal failure, acute and chronic cyclosporin-induced renal failure, cerebrovascular disease, myocardial ischemia, angina, heart failure, asthma, pulmonary hypertension, pulmonary hypertension secondary to intrinsic pulmonary disease, atherosclerosis, Raynaud's phenomenon, ulcers, sepsis, migraine, glaucoma, endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, cyclosporin induced renal failure and as an adjunct in angioplasty for prevention of restenosis, diabetes, preclampsia of pregnancy, bone remodeling, kidney transplant, male contraceptives, infertility and priaprism and benign prostatic hypertrophy.
Recent publications disclose that aryl and heteroaryl ring-fused cyclopentane derivatives have utility as endothelin receptor antagonists. See, e.g., International application Number PCT/US94/04603 (WO 94/25013) and U.S. Pat. No. 5,389,620. These particular publications also disclose synthetic approaches to the preparation of specific aryl and heteroaryl ring-fused cyclopentane derivatives, where those derivatives may function as endothelin receptor antagonists.
Unfortunately, the synthetic methods disclosed in the literature for making aryl and heteroaryl ring-fused cyclopentane derivatives do not provide for the desired products in high yield. Instead, the methods discussed in the literature require many steps, which are laborious and consequently expensive to conduct. Furthermore, when known methods provide for enantiomerically or diastereomerically pure products, they rely on chromatography to separate the various stereoisomers. Chromatography is far from a preferred approach in the preparation of isomerically pure materials on a commercial scale. Exemplary of this approach is the synthesis of (+) (1S,2R,3S) 3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop- 1-yloxy)indane-2-carboxylic acid and (+) (1S,2R,3S) 3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl-1-(3,4-methylenedioxyphenyl)-5 -(prop-1-yloxy)indane-2-carboxylic acid, which as set forth in WO 94/25013, is multi-step, low yielding and relies upon a chromatographic resolution of a racemic intermediate in order to prepare the named compounds in optically pure form.
A technique that needs to be developed in the synthetic art is the use of chiral aryl Grignard reagents. Chiral aryl Grignard reagents have seen some use as intermediates for the preparation of diastereomerically and enantiomerically pure compounds. Such chiral aryl Grignard reagents have been prepared, for example, from chiral oxazolidines derived from aryl aldehydes. See, e.g., Real, S. D. et al., U.S. Pat. No. 5,332,840 and Tet. Lett., 34, 8063-8066, 1993; Agami, C. et al., Tetrahedron, 41, 537-540, 1985; and Takahashi, H. et al., Synthesis, 681-682, 1992. Depending upon the reaction conditions, good to excellent diastereoselectivity has been reported for the addition of such chiral Grignard species to aldehydes, ketones and anhydrides. Aryl aldehydes have also been converted to chiral aryl Grignard reagents through formation of a homochiral acetal group adjacent to the Grignard reactive site. Such chiral materials have also been utilized in diastereoselective additions to carbonyl groups. See, e.g., Yamamoto, H. et al., Bull. Chem. Soc. Jap., 62, 3736-3738, 1989.
However, the utility of chiral aryl Grignard reagents derived from chiral aryl ethers, wherein a phenol has been protected with a suitable chiral protecting group has seen little, if any, practical application. In one example where a chiral aryl Grignard reagent was derived from a chiral aryl ether, and then reacted with a carbonyl compound, only a slight diastereoselectivity for the reaction might be inferred, but was not conclusively established. See Ronald et al., J. Org. Chem., 45, 2224-2229, 1980.
Thus, the preparation of chiral aryl Grignard reagents derived from chiral aryl ethers, and their use in the preparation of diastereomerically and enantiomerically pure compounds in the synthesis of aryl and heteroaryl ring fused cyclopentane derivatives, has not yet been established as viable synthetic methodology. Such methodology has utility in, for example, the preparation of endothelin receptor antagonists as disclosed in WO/9308799-A1 and U.S. Pat. No. 5,389,620, both of which are incorporated by reference herein, which to date have been prepared only via racemic mixtures of compounds, where chiral chromatography is necessary to obtain enantiomerically pure compounds. See, e.g., WO/9308799-A1. There is thus a need in the art to exploit chiral aryl Grignard reagents in the synthetic methodology useful in the preparation of enantiomerically and diastereomerically pure compounds that may be converted to endothelin receptor antagonists, and where the compounds are in enantiomerically or diastereomerically pure form without the need to resort to time-consuming and expensive chromatography.
Moreover, as explained more fully below, a preferred stereoselective synthesis of aryl and heteroaryl ring-fused cyclopentane derivatives will be able to place substituents at the three contiguous, non-ring fused carbons of the cyclopentane ring in a stereocontrolled manner. Furthermore, a preferred synthetic method will proceed in high overall yield, with minimal need to isolate and purify intermediates. This is a sophisticated challenge which is not met by any currently recognized synthetic methods.
There is thus a need in the art for an efficient synthetic method to prepare aryl and heteroaryl ring-fused cyclopentane derivatives, in completely or substantially enantiomerically or diastereomerically pure form, without the need to resort to chromatographic purification. In particular, there is a need in the art for methods to prepare (+) (1S,2R,3S) 3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop- 1-yloxy)indane-2-carboxylic acid and (+) (1 S,2R,3S) 3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)- 5-(prop-1-yloxy)indane-2-carboxylic acid, and pharmaceutically acceptable salts thereof, in an efficient and economical manner.
The numerous advantages of the presently invented processes and intermediates will become apparent upon review of the following description.